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Development of fetal hemoglobin inducers targeting epigenetic and oxidative stress mechanisms

针对表观遗传和氧化应激机制的胎儿血红蛋白诱导剂的开发

基本信息

批准号：
10385817
负责人：
Betty Sue Pace
金额：
$ 36.2万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385817
关键词：
Abnormal Hemoglobins Address Adherence Adolescent Adult Africa South of the Sahara Aminolevulinate Anemia Animal Model Annexins Antioxidants Apoptosis BACH1 gene Binding Biological Availability Biological Models Bone Marrow Butyric Acids CD34 gene Cells Chromatin Structure Clinical Clinical Research Clinical Trials Competitive Binding Country Data Decitabine Deoxyribonuclease I Development Disease Dose Drug Combinations Drug Kinetics Embryo Epigenetic Process Erythroid Cells Erythropoiesis Experimental Models FDA approved Fetal Development Fetal Hemoglobin Fright Fumarates Future Gene Activation Gene Expression Regulation Genes Genetic Genetic Transcription Goals Half-Life Hematological Disease Hematopoiesis Heme Hemoglobin Hemoglobinopathies Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Human Hypersensitivity Individual Infant Inherited Investigational Drugs Knockout Mice Knowledge Legal patent Locus Control Region Mediating Molecular Mus Names Oral Outcome Oxidative Stress Pain Papio Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase I Clinical Trials Phenotype Plasma Population Prodrugs Proteins Response Elements Rest Role Schedule Severities Sickle Cell Anemia Site Source Stains Stem cell transplant TFRC gene Testing Toxic effect Transgenic Mice Transgenic Organisms United States Work base beta Globin chemotherapy clinically relevant cost drug development drug efficacy effective therapy erythroid differentiation fetal gamma Globin gene therapy histone modification hydroxyurea improved in vivo inhibitor intravenous administration mouse model novel pre-clinical progenitor promoter sickle erythroid sickling small molecule stem cells translational impact translational study transplantation therapy

项目摘要

PROJECT SUMMARY The β-hemoglobinopathies are the most common genetic blood disorders worldwide, but limited effective treatments have been developed over the last three decades. Induction of normal, but developmentally silenced fetal hemoglobin (HbF) expression reduces anemia and ameliorates clinical severity of sickle cell disease (SCD). Histone deacetylases (HDACs) have been shown to promote silencing of the fetal γ-globin genes in adult erythroid cells, and HDAC inhibitors were shown to increase HbF in patients with β-hemoglobinopathies. But these had limitations for pharmaceutical application due to the need for intravenous administration and their anti- proliferative effects. This project focuses on creating safe and effective small-molecule oral HbF-inducing agents. In one study, we observed HbF induction with a novel oral conjugate of butyric acid (BA) and δ-aminolevulinate (ALA), named AN-233, and a BACH1 inhibitor that enhanced NRF2 expression in sickle erythroid progenitors and β-YAC mice. Next, focusing on these small-molecule agents, we will test the central hypothesis that modulation of γ-globin gene transcription through epigenetic histone modifications and enhanced NRF2 binding mediate HbF induction. Specific Aim 1. will test the prediction that the oral prodrug AN-233 induces HbF expression through epigenetic histone modifications and NRF2 activation, using relevant preclinical animal models. Treatments conducted in β-YAC and SCD transgenic mice will establish the optimal oral dose and schedule of AN233 that induces HbF without producing anti-proliferative effects. The phenotypic effects of AN-233 in SCD mice related to oxidative stress, and its anti-sickling ability will be tested. To achieve an indicator of human drug efficacy we will test AN-233 in anemic juvenile baboon to determine HbF induction and effects on hematopoiesis. We will define mechanisms of γ-globin activation by AN-233 involving epigenetic histone acetylation and the role of ALA in heme synthesis and NRF2 activation. Specific Aim 2. Test the prediction that the oral BACH1 inhibitor HPP-D enhances NRF2 binding to the γ-globin promoter ARE to activate transcription. We will establish the BACH1 inhibitor HPP-D, as an HbF inducer using sickle erythroid progenitors and conduct combination drug treatments with clinically relevant agents including hydroxyurea and decitabine. Subsequently, molecular mechanisms of HbF induction by HPP-D through enhanced NRF2 binding in the γ- globin promoter will be evaluated. Finally, the ability of HPP-D to induce HbF expression in the preclinical SCD mice will establish in vivo efficacy. Expected outcomes include establishing specific potent HDAC inhibitors and agents that modulate β-globin locus chromatin structure in favor of γ‐globin transcription, for subsequent clinical studies to address the unmet need for improved disease-modifying therapy for SCD.

项目摘要 β-血红蛋白病是世界范围内最常见的遗传性血液病，在过去的三十年中已经开发了治疗方法。诱导正常，但发育沉默胎儿血红蛋白（HbF）表达减少贫血并改善镰状细胞病（SCD）的临床严重性。组蛋白去乙酰化酶（HDACs）可促进胎儿γ-珠蛋白基因的沉默红系细胞和HDAC抑制剂显示增加β-血红蛋白病患者的HbF。但由于需要静脉内给药和它们的抗- 增殖效应该项目的重点是创造安全有效的小分子口服HbF诱导剂。在一项研究中，我们观察了丁酸（BA）和δ-氨基乙酰丙酸的新型口服缀合物对HbF的诱导作用。 (ALA)，命名为AN-233，和一种BACH 1抑制剂，其增强了镰状红系祖细胞中NRF 2的表达和β-YAC小鼠。接下来，我们将重点关注这些小分子药物，测试中心假设，即通过表观遗传组蛋白修饰和增强的NRF 2结合调节γ-珠蛋白基因转录介导HbF诱导。具体目标1.将测试口服前药AN-233诱导HbF的预测通过表观遗传组蛋白修饰和NRF 2激活表达，使用相关的临床前动物模型在β-YAC和SCD转基因小鼠中进行的治疗将确定最佳口服剂量以及诱导HbF而不产生抗增殖作用的AN 233的时间表。的表型效应 AN-233在SCD小鼠中与氧化应激相关，并且将测试其抗镰状化能力。为了达到一个指标，我们将在贫血的幼年狒狒中测试AN-233以确定HbF诱导和作用关于造血我们将定义AN-233激活γ-珠蛋白的机制，包括表观遗传组蛋白乙酰化和ALA在血红素合成和NRF 2活化中的作用。具体目标2。测试预测口服BACH 1抑制剂HPP-D增强NRF 2与γ-珠蛋白启动子ARE的结合，转录。我们将使用镰状红系祖细胞建立BACH 1抑制剂HPP-D作为HbF诱导剂并与临床相关的药剂（包括羟基脲和地西他滨）进行联合药物治疗。随后，研究了HPP-D通过增强NRF 2在γ-Alzheimer细胞中的结合诱导HbF的分子机制。将评估珠蛋白启动子。最后，HPP-D在临床前SCD中诱导HbF表达的能力被证实。小鼠将建立体内功效。预期的结果包括建立特异性有效的HDAC抑制剂，调节β-珠蛋白基因座染色质结构以有利于γ-珠蛋白转录的试剂，用于随后的临床研究，以解决改善SCD疾病缓解治疗的未满足需求。